The Actin Histidine methyltransferase SETD3 is a CHD1 lysine di-methyltransferase

Protein methylation is a widespread posttranslational modification that primarily targets lysine, arginine, and histidine residues. Aberrant protein methylation has been implicated in tumorigenesis, although the specific role of SETD3, a histidine methyltransferase, in cancer remains poorly understood. In this study, we identify CHD1 as a novel substrate of SETD3, which dimethylates CHD1 at lysine 209 (K209). Dimethylation at this site enhances CHD1 protein stability by reducing its ubiquitination. Furthermore, SETD3 mediates methylation of CHD1 to enhance H3K4me3 epigenetic marks and promote transcriptional activation of TNF-NFκB pathway genes. Collectively, our findings establish CHD1 as a new substrate for SETD3 and reveal a mechanism by which SETD3-mediated dimethylation of CHD1 at K209 promotes tumor progression.